Atrial fibrillation (AF) is the most common heart rhythm disturbance and the incidence is growing exponentially especially among older individuals. Once established, AF is associated with significant morbidity and mortality, and current treatment options are associated with limited long term success rates and significant risks. In this application, we propose to evaluate the balance of benefits and risks of marine omega-3 fatty acid (840 mg eicosapentaenoic acid [EPA] + docosahexaenoic acid [DHA]) and vitamin D3 (2,000 IU/day cholecalciferol) on AF incidence in the setting of an NIH-funded large-scale clinical trial, the Vitamin D and OmegA-3 TriaL (VITAL). VITAL is a randomized, double-blind, placebo-controlled, 2x2 factorial trial specifically designed to evaluate the efficacy of vitamin D3 and marine omega-3 fatty acid supplements in the primary prevention of cancer and cardiovascular disease among 20,000 men (aged 50+ years) and women (aged 55+ years). Based upon data in cellular, animal, and human studies, both of the study agents have the potential to influence arrhythmic risk in general and AF risk specifically, both positively and negatively. However, definitive data from randomized trials are lacking, particularly with respect to primary prevention. In this application, we propose an ancillary study to ascertain and adjudicate AF outcomes for the primary aim of testing whether omega-3 fatty acid and/or vitamin D3 supplementation influences AF risk in an older population, where the incidence of AF is growing substantially. Case validation of incident AF will involve systematic ascertainment of physician diagnoses of AF on annual study questionnaires supplemented by CMS linkage followed by collection of detailed diagnostic information from outpatient and inpatient medical records. An endpoint committee composed of cardiologists will confirm incident AF events based on medical record review. As a secondary aim of the proposal, electrocardiograms will also be obtained at baseline and again after two years of treatment and follow-up among a sub-cohort of 1000 patients evaluated at the VITAL Clinical and Translational Science Center to assess whether and to what extent vitamin D3 or omega-3 supplementation might impact electrocardiographic parameters, which could serve as intermediate phenotypes for heart rhythm disorders. To address tertiary aims, detailed information on timing and mechanism of death will also be collected in the entire cohort to explore treatment effects on arrhythmic death, and EPA/DHA along with 25(OH) vitamin D levels will be measured in baseline blood samples in a nested case-cohort design to explore if baseline levels modify treatment effects on AF incidence. In summary, we propose a timely and cost-effective strategy that takes advantage of the enormous investment of resources and infrastructure in the VITAL trial to provide much needed data on the summation of benefits and risks of these agents on AF incidence as well as other arrhythmic endpoints. If either agent significantly lowers AF risk, then these agents would represent one of the first therapies proven effective for the primary prevention of this growing morbid disease.